The present invention relates to a method of detecting neuromuscular disease in a patient, particularly Leber's hereditary optic neuropathy. More particularly, the invention relates to the detection of a point mutation at the mitochondrial DNA nucleotide position 11778 in the patient's DNA.
Leber's hereditary optic neuropathy (LHON) is associated with a rapid bilateral loss of central vision caused by neuroretinal degeneration. The median age at the onset of vision loss is 20 to 24 years, but ranges from adolescence to late adulthood. Cardiac dysrhythmias are also a frequent manifestation. In numerous large pedigrees, LHON patients have been found to be related exclusively through the maternal lineage. However, in most pedigrees, expression is variable and there is a bias toward males exhibiting ophthalmological problems.
Human mitochondrial DNA (mtDNA) is also maternally inherited. Each cell contains thousands of copies of mtDNA in the matrixes of the mitochondria. Each mtDNA codes for a large and a small ribosomal RNA, 22 transfer RNA's, and 13 polypeptides that function in the enzyme complexes of oxidative phosphorylation, including subunit 4 of NADH dehydrogenase.
A broad spectrum of neuromuscular diseases has recently been associated with alterations in mitochondrial structure and in the capacity to generate ATP. Some of these "mitochondrial encephalomyopathies," such as LHON, primarily affect the central nervous system, but others, such as myoclonus epilepsy and ragged red fiber disease (MERRF) or mitochondrial encephalomyopathy lacticacidoses and stroke-like symptoms (MELAS), affect the skeletal muscle, heart, kidney, and liver as well. Diagnoses of multiple sclerosis and LHON may be sometimes confused.
Prior to this invention, no method was known for the molecular diagnosis of LHON or associated diseases. Therefore, there exists a need to establish the molecular cause of such disease and to provide a specific molecular test to accurately diagnose the presence of or susceptibility to the disease in a patient.